The purpose of this project is twofold: first to determine the molecular basis of chromosome rearrangements underlying the genesis and progression of human malignant melanoma. The second, to identify novel genes associated with melanoma susceptibility in hereditary families. Melanoma has the fastest growing rate of incidence of any cancer (next to lung cancer in women) in the Western world, and extraordinarily little is known about the molecular genetic changes underlying this important disease. This project can be divided into four component parts. 1) Molecular analysis of tumor progression. [This focuses on clonal progression identified by tissue dissection and comparative genomic hybridization, and on clonal karyotypic alterations in malignant melanoma]. 2) Identification of genes differentially expressed during growth, differentiation and progression. [This focuses on suppression of tumorigenicity of chromosome 6, cDNA subtraction/differential display, retroviral- mediated reversion of tumor suppression, and DNA microarray analysis of differential gene expression]. 3) Genomic analysis of chromosome 6 alterations. [This involves microdissection- based cloning of chromosomal breakpoints in melanoma, and other malignancies]. 4) Analysis of susceptibility loci in hereditary melanoma families using linkage analysis.